Synthetic phenotype

Fukuda, N., Hu, W. Y., Satoh, C., et al. 1999. Contribution of synthetic phenotype on the enhanced angiotensin II-generating system in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens 17 1099-1107. 

In addition to cell migration, another characteristic function of the VSM synthetic phenotype is proliferation. CaMKII has been implicated in cell cycle control in a number of systems, but investigations in this area have yield mixed results. Most studies to date have relied on pharmacological inhibitors of CaMKII such as KN-62 or KN-93 (Tombes et al. 1995) and point to a positive role for CaMKII in mediating the cell cycle. Conversely, overexpression of a constitutively active mutant of CaMKIIa. suggested a negative role for kinase (Beauman et al. 2003). Interpretation of the latter studies is complicated by potential nonspecific effects... 

Kessler D, Dethlefsen S, Haase I, Plomann M, Hirche F, Krieg T, Eckes B. Fibroblasts in mechanically stressed collagen lattices assume a synthetic phenotype. J Biol Chem. 2001 237 159-172. 

Changes in the composition of extracellular milieu can have profound consequences on the differentiation profile of SMC. The high responsiveness of SMC to specific environmental cues coupled with the inherent phenotypic instability of SMC give rise to SMC showing the so-called synthetic phenotype, i.e., SMC almost deprived of myofilaments and enriched in organelles deputed to synthesis of ECM proteins... 

It is generally accepted that when vascular SMC are grown in vitro they lose to a various extent their peculiar contractile features in favor of the synthetic phenotype (see Section 6.2). Recent results of cell cloning experiments on aortic SM tissue from adult and newborn rats point, however, to the existence of multiple and phenotypically stable SMC phenotypes in vivo and could furnish a biological justification for SMC heterogeneity found with the differentiation markers. Unlike some SMC lines, these clones are derived from plating at different densities and not via mutagenesis, transformation [235,236] or from conditionally immortalized cells [237]. 

Numerous laboratories have observed that the cell structure as well as cytoskeletal and cytocontractile protein content is markedly different between the two opposite SMC phenotypes. In the synthetic phenotype SM2, and to a lesser extent SMI, SM-type a-actin, h-caldesmon, calponin and desmin content/distribution are decreased, whereas NM-type MyHC-... 

Several factors are considered important in the transformation to a synthetic phenotype ... 

SMCs develop hypomethylation in vitro during transformation from a contractile to a synthetic phenotype. Genomic hypomethylation occurs during atherogenesis in human, mouse, and rabbit lesions, and it correlates with increased transcriptional activity. Also, methyltransferase is expressed in atherosclerotic lesion and hypomethylation is present in advanced lesions and may reflect cellular proliferation and gene expression in atherosclerotic lesions (245). 

Poly amines such as putrescine, spermidine, and spermine are involved in the transition of migrated VSMC into a synthetic phenotype (226). 

Kessler, D., S. Dethlefsen, 1. Haase et al. 2001. Fibroblasts in mechanically stressed coUagen lattices assume a synthetic phenotype. /Biol Chem 276(39) 36575-85. 

Keywords— Smooth muscle cells, Coutractile phenotype. Synthetic phenotype. Extracellular matrix, lutegriu expression. 

We have adapted this logic to identify small molecules, genes, or pathways that functionally interact with disease alleles. By analogy to genetic interaction screens, the first hit is a mutation in a gene of interest, such as a gene that influences disease susceptibility. The second hit is a small molecule with characterized mechanism(s), such as an FDA-approved drug or a tool compound (e.g., a kinase inhibitor). A synthetic phenotype can then be observed when a small molecule causes a qualitatively or quantitatively distinct phenotype in the presence of a wild-type... 

Fig. 1 Analogy between genetic interaction screens in model organisms and chemicaligenetic interaction screen in patient-derived cells. In the latter, the second hit is provided by a small molecule with characterized mechanism the synthetic phenotype is manifest as an assay phenotype that is distinct in mutant versus wild-type cells...

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